rs10264272

Variant names:

• chr7-99665212-C-T
• rs10264272
• NM_000777.5:c.624G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_000777.5(CYP3A5):​c.624G>A​(p.Lys208Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00746 in 1,614,048 control chromosomes in the GnomAD database, including 653 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.037 (324 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (329 hom.)
• Consequence: CYP3A5 NM_000777.5 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.86
• Publications: 215 publications found

Genes affected

CYP3A5 (HGNC:2638): (cytochrome P450 family 3 subfamily A member 5) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. The encoded protein metabolizes drugs as well as the steroid hormones testosterone and progesterone. This gene is part of a cluster of cytochrome P450 genes on chromosome 7q21.1. Two pseudogenes of this gene have been identified within this cluster on chromosome 7. Expression of this gene is widely variable among populations, and a single nucleotide polymorphism that affects transcript splicing has been associated with susceptibility to hypertensions. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2014]

ZSCAN25 (HGNC:21961): (zinc finger and SCAN domain containing 25) This gene encodes a protein that bears some similarity to zinc finger proteins, which are involved in DNA binding and protein-protein interactions. Multiple alternatively spliced transcript variants have been identified, but the full-length nature for most of them has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 7-99665212-C-T is Benign according to our data. Variant chr7-99665212-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3039123.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=1.86 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP3A5	NM_000777.5	c.624G>A	p.Lys208Lys	synonymous_variant	Exon 7 of 13	ENST00000222982.8	NP_000768.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP3A5	ENST00000222982.8	c.624G>A	p.Lys208Lys	synonymous_variant	Exon 7 of 13	1	NM_000777.5	ENSP00000222982.4

Frequencies

GnomAD3 genomes AF: 0.0370 AC: 5627 AN: 152130 Hom.: 317 Cov.: 32

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.0315

GnomAD2 exomes AF: 0.0100 AC: 2524 AN: 251422 AF XY: 0.00715

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.00778

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000853

Gnomad OTH exome AF: 0.00733

GnomAD4 exome AF: 0.00436 AC: 6376 AN: 1461800 Hom.: 329 Cov.: 30 AF XY: 0.00385 AC XY: 2802 AN XY: 727214

African (AFR) AF: 0.133 AC: 4442 AN: 33464

American (AMR) AF: 0.00955 AC: 427 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000429 AC: 37 AN: 86254

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53418

Middle Eastern (MID) AF: 0.0118 AC: 68 AN: 5768

European-Non Finnish (NFE) AF: 0.000702 AC: 781 AN: 1111952

Other (OTH) AF: 0.0102 AC: 619 AN: 60392

GnomAD4 genome AF: 0.0372 AC: 5660 AN: 152248 Hom.: 324 Cov.: 32 AF XY: 0.0360 AC XY: 2678 AN XY: 74456

African (AFR) AF: 0.124 AC: 5170 AN: 41536

American (AMR) AF: 0.0228 AC: 349 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.000941 AC: 64 AN: 68004

Other (OTH) AF: 0.0312 AC: 66 AN: 2114

Alfa AF: 0.0124 Hom.: 423

Bravo AF: 0.0425

Asia WGS AF: 0.0120 AC: 40 AN: 3478

EpiCase AF: 0.00136

EpiControl AF: 0.00107

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

CYP3A5-related disorder Benign:1

Jul 21, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	5.2
DANN	Benign	0.34
PhyloP100		1.9
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10264272; hg19: chr7-99262835;